The High Blood Pressure-Malaria Protection Hypothesis.

RATIONALE: A recently proposed hypothesis states that malaria may contribute to hypertension in endemic areas,1 but the role of angiotensin II (Ang II), a major regulator of blood pressure, was not considered. Elevated levels of Ang II may confer protection against malaria morbidity and mortality, providing an alternative explanation for hypertension in malaria endemic areas. OBJECTIVE: To discuss a possible alternative cause for hypertension in populations who have been under the selective pressure of malaria. METHODS AND RESULTS: We reviewed published scientific literature for studies that could establish a link between Ang II and malaria. Both genetic and functional studies suggested that high levels of Ang II may confer protection against cerebral malaria by strengthening the integrity of the endothelial brain barrier. We also describe strong experimental evidence supporting our hypothesis through genetic, functional, and interventional studies. CONCLUSIONS: A causal association between high levels of Ang II and protection from malaria pathogenesis can provide a likely explanation for the increased prevalence in hypertension observed in populations of African and South Asian origin. Furthermore, this potential causative connection might also direct unique approaches for the effective treatment of cerebral malaria.

Animal Models and "Omics" Technologies for Identification of Novel Biomarkers and Drug Targets to Prevent Heart Failure.

It is now accepted that heart failure (HF) is a complex multifunctional disease rather than simply a hemodynamic dysfunction. Despite its complexity, stressed cardiomyocytes often follow conserved patterns of structural remodelling in order to adapt, survive, and regenerate. When cardiac adaptations cannot cope with mechanical, ischemic, and metabolic loads efficiently or become chronically activated, as, for example, after infection, then the ongoing structural remodelling and dedifferentiation often lead to compromised pump function and patient death. It is, therefore, of major importance to understand key events in the progression from a compensatory left ventricular (LV) systolic dysfunction to a decompensatory LV systolic dysfunction and HF. To achieve this, various animal models in combination with an "omics" toolbox can be used. These approaches will ultimately lead to the identification of an arsenal of biomarkers and therapeutic targets which have the potential to shape the medicine of the future.

Characterization of the brain-specific non-AT(1), non-AT(2) angiotensin binding site in the mouse.

In the present study the existence of a non-AT(1), non-AT(2) angiotensin (Ang) binding site unmasked by the organomercurial protease inhibitor p-chloromercuribenzoate (PCMB) was demonstrated in mouse brain membranes, consistent with observations previously reported in the rat (Karamyan and Speth, 2007b). The pharmacological specificity of the non-AT(1), non-AT(2) angiotensin binding site was similar to the rat brain: Sar(1)-Ile(8)-Ang II > Ang III >or= Ang II > Ang I> p-aminophenylalanine(6) Ang II> CGP42112 >> Ang IV > Ang 1-7 congruent with shorter angiotensin fragments. Neurotensin, bradykinin, and luteinizing hormone-releasing hormone showed K(i) values >10 microM, while substance P and VIP had K(i) values of approximately 2 microM. The non-AT(1), non-AT(2) angiotensin binding site was not present in adrenal, liver or kidney. Subcellular fractionation showed a higher density of [(125)I]Ang II binding in plasma membrane (P2) fractions of cerebral cortex and hypothalamus relative to debris (P1) fractions. The binding site is present in the brains of mice in which the AT(1a), AT(1b), AT(2), Mas, and neprilysin (EC 3.4.24.11, neutral endopeptidase) was knocked out confirming that the binding site is not a heretofore described angiotensin receptor or neprilysin. These observations confirm that this novel Ang binding site is distinct from classical AT(1), AT(2), AT(4) and Ang 1-7 receptors while retaining a high specificity for angiotensins that act on the known angiotensin receptors. Whether this binding site functions as a novel receptor for angiotensins or a specific angiotensinase with variable functionality at different redox states will require further study.